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    A2ML1 alpha-2-macroglobulin like 1 [ Homo sapiens (human) ]

    Gene ID: 144568, updated on 10-Dec-2024

    Summary

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    Official Symbol
    A2ML1provided by HGNC
    Official Full Name
    alpha-2-macroglobulin like 1provided by HGNC
    Primary source
    HGNC:HGNC:23336
    See related
    Ensembl:ENSG00000166535 MIM:610627; AllianceGenome:HGNC:23336
    Gene type
    protein coding
    RefSeq status
    REVIEWED
    Organism
    Homo sapiens
    Lineage
    Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo
    Also known as
    OMS; p170; CPAMD9
    Summary
    This gene encodes a member of the alpha-macroglobulin superfamily. The encoded protein is thought to be an N-glycosylated monomeric protein that acts as an inhibitor of several proteases. It has been shown to form covalent interactions with proteases, and has been reported as the p170 antigen recognized by autoantibodies in the autoimmune disease paraneoplastic pemphigus (PNP; PMID:20805888). Mutations in these gene have also been associated with some cases of Noonan syndrome (NS; PMID:24939586) as well as some cases of otitis media (PMID:26121085). Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Aug 2015]
    Expression
    Restricted expression toward esophagus (RPKM 190.0) See more
    Orthologs
    all
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    Genomic context

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    See A2ML1 in Genome Data Viewer
    Location:
    12p13.31
    Exon count:
    40
    Annotation release Status Assembly Chr Location
    RS_2024_08 current GRCh38.p14 (GCF_000001405.40) 12 NC_000012.12 (8822621..8887459)
    RS_2024_08 current T2T-CHM13v2.0 (GCF_009914755.1) 12 NC_060936.1 (8805910..8869474)
    RS_2024_09 previous assembly GRCh37.p13 (GCF_000001405.25) 12 NC_000012.11 (8975217..9029383)

    Chromosome 12 - NC_000012.12Genomic Context describing neighboring genes Neighboring gene ribosomal modification protein rimK like family member B Neighboring gene H3K27ac hESC enhancer GRCh37_chr12:8924703-8925204 Neighboring gene H3K27ac hESC enhancer GRCh37_chr12:8925205-8925704 Neighboring gene ribosomal protein SA pseudogene 51 Neighboring gene NANOG-H3K27ac-H3K4me1 hESC enhancer GRCh37_chr12:8940201-8940740 Neighboring gene NANOG-H3K27ac-H3K4me1 hESC enhancer GRCh37_chr12:8940741-8941280 Neighboring gene NANOG-H3K27ac-H3K4me1 hESC enhancer GRCh37_chr12:8941281-8941820 Neighboring gene NANOG-H3K27ac hESC enhancer GRCh37_chr12:8941899-8942576 Neighboring gene NANOG-H3K27ac hESC enhancer GRCh37_chr12:8942577-8943254 Neighboring gene H3K27ac hESC enhancer GRCh37_chr12:8947958-8948568 Neighboring gene A2ML1 antisense RNA 1 Neighboring gene NANOG-H3K27ac-H3K4me1 hESC enhancer GRCh37_chr12:8957581-8958288 Neighboring gene H3K27ac hESC enhancer GRCh37_chr12:8958995-8959702 Neighboring gene OCT4-NANOG-H3K27ac-H3K4me1 hESC enhancer GRCh37_chr12:8962654-8963394 Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr12:8963395-8964136 Neighboring gene long intergenic non-protein coding RNA 2972 Neighboring gene H3K27ac hESC enhancer GRCh37_chr12:8967023-8967549 Neighboring gene Sharpr-MPRA regulatory region 8322 Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr12:8980966-8981708 Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr12:8984681-8985424 Neighboring gene H3K27ac hESC enhancer GRCh37_chr12:9057572-9058228 Neighboring gene NANOG-H3K27ac-H3K4me1 hESC enhancer GRCh37_chr12:9060851-9061506 Neighboring gene OCT4-NANOG-H3K27ac hESC enhancer GRCh37_chr12:9064238-9064790 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 4218 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 4219 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 4220 Neighboring gene H3K27ac hESC enhancer GRCh37_chr12:9101505-9102410 Neighboring gene H3K27ac hESC enhancer GRCh37_chr12:9102411-9103315 Neighboring gene MED14-independent group 3 enhancer GRCh37_chr12:9108425-9109624 Neighboring gene polyhomeotic homolog 1 Neighboring gene mannose-6-phosphate receptor, cation dependent Neighboring gene killer cell lectin like receptor G1 Neighboring gene heterogeneous nuclear ribonucleoprotein A1 pseudogene 34

    Genomic regions, transcripts, and products

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    Go to nucleotide: Graphics FASTA GenBank

    Expression

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    • Project title: HPA RNA-seq normal tissues
    • Description: RNA-seq was performed of tissue samples from 95 human individuals representing 27 different tissues in order to determine tissue-specificity of all protein-coding genes
    • BioProject: PRJEB4337
    • Publication: PMID 24309898
    • Analysis date: Wed Apr 4 07:08:55 2018

    Bibliography

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    Related articles in PubMed

    1. A2ML1 Inhibits Esophageal Squamous Cell Carcinoma Progression and Serves as a Novel Prognostic Biomarker. Zhang X, et al. Can J Gastroenterol Hepatol, 2023. PMID 37954860, Free PMC Article
    2. External ear anomalies and hearing impairment in Noonan Syndrome. van Trier DC, et al. Int J Pediatr Otorhinolaryngol, 2015 Jun. PMID 25862627
    3. Genetic and Environmental Determinants of Otitis Media in an Indigenous Filipino Population. Santos-Cortez RL, et al. Otolaryngol Head Neck Surg, 2016 Nov. PMID 27484237, Free PMC Article
    4. Middle ear microbiome differences in indigenous Filipinos with chronic otitis media due to a duplication in the A2ML1 gene. Santos-Cortez RL, et al. Infect Dis Poverty, 2016 Nov 1. PMID 27799062, Free PMC Article
    5. A2ML1 and otitis media: novel variants, differential expression, and relevant pathways. Larson ED, et al. Hum Mutat, 2019 Aug. PMID 31009165, Free PMC Article

    See all (50) citations in PubMed

    GeneRIFs: Gene References Into Functions

    What's a GeneRIF?
    1. A2ML1 Inhibits Esophageal Squamous Cell Carcinoma Progression and Serves as a Novel Prognostic Biomarker.
      Title: A2ML1 Inhibits Esophageal Squamous Cell Carcinoma Progression and Serves as a Novel Prognostic Biomarker.
    2. Audiologic Measures in an Indigenous Community with A2ML1- and FUT2-Related Otitis Media.
      Title: Audiologic Measures in an Indigenous Community with A2ML1- and FUT2-Related Otitis Media.
    3. Cryo-EM structures of human A2ML1 elucidate the protease-inhibitory mechanism of the A2M family.
      Title: Cryo-EM structures of human A2ML1 elucidate the protease-inhibitory mechanism of the A2M family.
    4. The clinical significance of A2ML1 variants in Noonan syndrome has to be reconsidered.
      Title: The clinical significance of A2ML1 variants in Noonan syndrome has to be reconsidered.
    5. Study identified 16 novel A2ML1 variants in otitis media patients, two of which are pathogenic further providing evidence to support a role for A2ML1 in middle ear mucosal pathology. Sequencing of patients salivary RNA samples demonstrated lower A2ML1 expression according to the carriage of A2ML1 variants.
      Title: A2ML1 and otitis media: novel variants, differential expression, and relevant pathways.
    6. The functional assessment supported the pathogenicity of the RAF1 and RIT1 variants of unknown significance (VUSs), while the significance of two VUSs in A2ML1 remained unclear.
      Title: Integrating Functional Analysis in the Next-Generation Sequencing Diagnostic Pipeline of RASopathies.
    7. Brain gene expression of PADI2, ZNF385A, PSD2, and A2ML1 and DNA methylation dysregulations are implicated in the alteration of brain tissue properties associated with late-life cognitive decline above and beyond the influence of common neuropathologic conditions.
      Title: Association Between Brain Gene Expression, DNA Methylation, and Alteration of Ex Vivo Magnetic Resonance Imaging Transverse Relaxation in Late-Life Cognitive Decline.
    8. The indigenous Filipino population has a ~50% prevalence of otitis media. A2ML1 genotype is the primary risk factor for otitis media and main determinant of disease progression, although age, the middle ear microbiome, and social clusters might modulate the effect of the A2ML1 genotype.
      Title: Genetic and Environmental Determinants of Otitis Media in an Indigenous Filipino Population.
    9. A2ML1-related otitis media susceptibility may be mediated by changes in the middle ear microbiome.
      Title: Middle ear microbiome differences in indigenous Filipinos with chronic otitis media due to a duplication in the A2ML1 gene.
    10. Studies support a role for alpha-2-macroglobulin-like 1 protein (A2ML1) in the pathophysiology of otitis media.
      Title: Rare A2ML1 variants confer susceptibility to otitis media.
    Submit: New GeneRIF Correction See all GeneRIFs (15)

    Phenotypes

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    Find tests for this gene in the NIH Genetic Testing Registry (GTR)

    Review eQTL and phenotype association data in this region using PheGenI

    Associated conditions

    Description Tests
    Otitis media, susceptibility to
    MedGen: C1833692 OMIM: 166760 GeneReviews: Not available
    		Compare labs

    EBI GWAS Catalog

    Description
    Discovery and refinement of loci associated with lipid levels.
    EBI GWAS Catalog

    Variation

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    See variants in ClinVar

    See studies and variants in dbVar

    See Variation Viewer (GRCh37.p13)

    See Variation Viewer (GRCh38)

    Interactions

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    Products Interactant Other Gene Complex Source Pubs Description

    General gene information

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    Markers

    Homology

    Clone Names

    • FLJ16045, FLJ25179, FLJ39129, FLJ41597, FLJ41598, FLJ41607, DKFZp686C1729, DKFZp686D2011, DKFZp686G1812, DKFZp686L1821, DKFZp686O1010

    Gene Ontology Provided by GOA

    Function Evidence Code Pubs
    enables peptidase inhibitor activity IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    enables serine-type endopeptidase inhibitor activity IEA
    Inferred from Electronic Annotation
    more info
    		  
    Process Evidence Code Pubs
    involved_in regulation of endopeptidase activity IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    Component Evidence Code Pubs
    located_in extracellular exosome HDA PubMed 
    located_in extracellular space IDA
    Inferred from Direct Assay
    more info
    		 PubMed 

    General protein information

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    Preferred Names
    alpha-2-macroglobulin-like protein 1
    Names
    C3 and PZP-like, alpha-2-macroglobulin domain containing 9

    NCBI Reference Sequences (RefSeq)

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    RefSeqs maintained independently of Annotated Genomes

    These reference sequences exist independently of genome builds. Explain

    These reference sequences are curated independently of the genome annotation cycle, so their versions may not match the RefSeq versions in the current genome build. Identify version mismatches by comparing the version of the RefSeq in this section to the one reported in Genomic regions, transcripts, and products above.

    Genomic

    1. NG_042857.2 RefSeqGene

      Range
      5002..59168
      Download
      GenBank, FASTA, Sequence Viewer (Graphics)

    mRNA and Protein(s)

    1. NM_001282424.3 → NP_001269353.2  alpha-2-macroglobulin-like protein 1 isoform 2

      Status: REVIEWED

      Description
      Transcript Variant: This variant (2) represents use of an alternate promoter, and thus differs in the 5' UTR and 5' coding region, compared to variant 1. These differences cause translation initiation at an alternate AUG, and the resulting isoform (2) has a distinct and shorter N-terminus compared to isoform 1.
      Source sequence(s)
      AC006513, AC006581
      Consensus CDS
      CCDS73439.1
      UniProtKB/TrEMBL
      H0YGG5
      Related
      ENSP00000438292.1, ENST00000539547.5
      Conserved Domains (4) summary
      cd02897
      Location:465 → 760
      A2M_2; Proteins similar to alpha2-macroglobulin (alpha (2)-M). This group also contains the pregnancy zone protein (PZP). Alpha(2)-M and PZP are broadly specific proteinase inhibitors. Alpha (2)-M is a major carrier protein in serum. The structural thioester ...
      pfam00207
      Location:245 → 335
      A2M; Alpha-2-macroglobulin family
      pfam07677
      Location:871 → 958
      A2M_recep; A-macroglobulin receptor
      pfam07703
      Location:1 → 110
      A2M_N_2; Alpha-2-macroglobulin family N-terminal region

    2. NM_144670.6 → NP_653271.3  alpha-2-macroglobulin-like protein 1 isoform 1 precursor

      Status: REVIEWED

      Description
      Transcript Variant: This variant (1) represents the longer transcript and encodes the longer isoform (1).
      Source sequence(s)
      AC006513, AC006581
      Consensus CDS
      CCDS8596.2
      UniProtKB/Swiss-Prot
      A8K2U0, B5MDD1, B7Z7V4, D3DUV3, F5H2Z2, Q2M224, Q6ZW52, Q6ZW53, Q8N1M4, Q96LQ8
      UniProtKB/TrEMBL
      B3KVV6
      Related
      ENSP00000299698.7, ENST00000299698.12
      Conserved Domains (5) summary
      cd02897
      Location:956 → 1251
      A2M_2; Proteins similar to alpha2-macroglobulin (alpha (2)-M). This group also contains the pregnancy zone protein (PZP). Alpha(2)-M and PZP are broadly specific proteinase inhibitors. Alpha (2)-M is a major carrier protein in serum. The structural thioester ...
      pfam00207
      Location:736 → 826
      A2M; Alpha-2-macroglobulin family
      pfam01835
      Location:122 → 211
      A2M_N; MG2 domain
      pfam07677
      Location:1362 → 1449
      A2M_recep; A-macroglobulin receptor
      pfam07703
      Location:459 → 601
      A2M_N_2; Alpha-2-macroglobulin family N-terminal region

    RefSeqs of Annotated Genomes: GCF_000001405.40-RS_2024_08

    The following sections contain reference sequences that belong to a specific genome build. Explain

    Reference GRCh38.p14 Primary Assembly

    Genomic

    1. NC_000012.12 Reference GRCh38.p14 Primary Assembly

      Range
      8822621..8887459
      Download
      GenBank, FASTA, Sequence Viewer (Graphics)

    mRNA and Protein(s)

    1. XM_011520566.3 → XP_011518868.1  alpha-2-macroglobulin-like protein 1 isoform X1

      See identical proteins and their annotated locations for XP_011518868.1

      UniProtKB/TrEMBL
      B3KVV6
      Conserved Domains (7) summary
      COG2373
      Location:123 → 1055
      YfaS; Uncharacterized conserved protein YfaS, alpha-2-macroglobulin family [General function prediction only]
      cd02897
      Location:969 → 1264
      A2M_2; Proteins similar to alpha2-macroglobulin (alpha (2)-M). This group also contains the pregnancy zone protein (PZP). Alpha(2)-M and PZP are broadly specific proteinase inhibitors. Alpha (2)-M is a major carrier protein in serum. The structural thioester ...
      pfam00207
      Location:749 → 839
      A2M; Alpha-2-macroglobulin family
      pfam01835
      Location:122 → 211
      A2M_N; MG2 domain
      pfam07677
      Location:1375 → 1462
      A2M_recep; A-macroglobulin receptor
      pfam07678
      Location:1021 → 1266
      A2M_comp; A-macroglobulin complement component
      pfam07703
      Location:455 → 613
      A2M_N_2; Alpha-2-macroglobulin family N-terminal region

    2. XM_047428387.1 → XP_047284343.1  alpha-2-macroglobulin-like protein 1 isoform X4

      UniProtKB/TrEMBL
      B3KVV6

    3. XM_011520567.3 → XP_011518869.1  alpha-2-macroglobulin-like protein 1 isoform X1

      See identical proteins and their annotated locations for XP_011518869.1

      UniProtKB/TrEMBL
      B3KVV6
      Conserved Domains (7) summary
      COG2373
      Location:123 → 1055
      YfaS; Uncharacterized conserved protein YfaS, alpha-2-macroglobulin family [General function prediction only]
      cd02897
      Location:969 → 1264
      A2M_2; Proteins similar to alpha2-macroglobulin (alpha (2)-M). This group also contains the pregnancy zone protein (PZP). Alpha(2)-M and PZP are broadly specific proteinase inhibitors. Alpha (2)-M is a major carrier protein in serum. The structural thioester ...
      pfam00207
      Location:749 → 839
      A2M; Alpha-2-macroglobulin family
      pfam01835
      Location:122 → 211
      A2M_N; MG2 domain
      pfam07677
      Location:1375 → 1462
      A2M_recep; A-macroglobulin receptor
      pfam07678
      Location:1021 → 1266
      A2M_comp; A-macroglobulin complement component
      pfam07703
      Location:455 → 613
      A2M_N_2; Alpha-2-macroglobulin family N-terminal region

    4. XM_017018869.2 → XP_016874358.1  alpha-2-macroglobulin-like protein 1 isoform X2

      UniProtKB/TrEMBL
      B3KVV6

    5. XM_017018870.2 → XP_016874359.1  alpha-2-macroglobulin-like protein 1 isoform X3

      UniProtKB/Swiss-Prot
      A8K2U0, B5MDD1, B7Z7V4, D3DUV3, F5H2Z2, Q2M224, Q6ZW52, Q6ZW53, Q8N1M4, Q96LQ8
      UniProtKB/TrEMBL
      B3KVV6
      Conserved Domains (5) summary
      cd02897
      Location:956 → 1251
      A2M_2; Proteins similar to alpha2-macroglobulin (alpha (2)-M). This group also contains the pregnancy zone protein (PZP). Alpha(2)-M and PZP are broadly specific proteinase inhibitors. Alpha (2)-M is a major carrier protein in serum. The structural thioester ...
      pfam00207
      Location:736 → 826
      A2M; Alpha-2-macroglobulin family
      pfam01835
      Location:122 → 211
      A2M_N; MG2 domain
      pfam07677
      Location:1362 → 1449
      A2M_recep; A-macroglobulin receptor
      pfam07703
      Location:459 → 601
      A2M_N_2; Alpha-2-macroglobulin family N-terminal region

    RNA

    1. XR_931275.2 RNA Sequence

    2. XR_001748594.2 RNA Sequence

    Alternate T2T-CHM13v2.0

    Genomic

    1. NC_060936.1 Alternate T2T-CHM13v2.0

      Range
      8805910..8869474
      Download
      GenBank, FASTA, Sequence Viewer (Graphics)

    mRNA and Protein(s)

    1. XM_054371194.1 → XP_054227169.1  alpha-2-macroglobulin-like protein 1 isoform X1

      UniProtKB/TrEMBL
      B3KVV6

    2. XM_054371198.1 → XP_054227173.1  alpha-2-macroglobulin-like protein 1 isoform X4

      UniProtKB/TrEMBL
      B3KVV6

    3. XM_054371195.1 → XP_054227170.1  alpha-2-macroglobulin-like protein 1 isoform X1

      UniProtKB/TrEMBL
      B3KVV6

    4. XM_054371196.1 → XP_054227171.1  alpha-2-macroglobulin-like protein 1 isoform X2

      UniProtKB/TrEMBL
      B3KVV6

    5. XM_054371197.1 → XP_054227172.1  alpha-2-macroglobulin-like protein 1 isoform X3

      UniProtKB/TrEMBL
      B3KVV6

    RNA

    1. XR_008488540.1 RNA Sequence

    2. XR_008488539.1 RNA Sequence

    Nucleotide Protein
    Heading Accession and Version
    Protein Accession Links
    GenPept Link UniProtKB Link
    A8K2U0.3 GenPept UniProtKB/Swiss-Prot:A8K2U0

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